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Cell Cycle
written by Michael
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The RB1 Problem

Patients of leiomyosarcoma have been known to have abnormalities with the RB1 gene. A similar problem occurs within other sarcomas but mostly in leiomyosarcoma, malignant fibrous histiocytoma (MFH) and rhabdomyosarcoma.

How RB1 works

The result of cell division should be a cloned cell that has the exact same DNA as its parent cell. Cell division is normally allowed to proceed only once the DNA has been proof read and is confirmed to be an exact match. The proof reading is done by enzymes who can repair DNA that hasn't been accurately copied. If the newer DNA is not an exact mirror of the older DNA then enzymes will remove the newer DNA allowing the older DNA to be recopied.

The cell knows that it is still proof reading by the presence of the Rb protein that is created by the RB1 gene. The Rb protein is like a switch telling the cell to wait until proof reading is completed. When the cell has completed the proof reading phase and corrected all the errors, the Rb protein is phosphorylated allowing the cell to continue on to the next phase of cell division.

This diagram shows the cascading events leading to the phosphorylation of Rb protein.
geneti2.jpg

Rb protein is directly phosphorylated by one of four proteins (Cyclin D1, D2, D3 or E). These Cyclins are controlled by a family of proteins called Cyclin Dependent Kinases (CDKs). Two of these (CDK4 and CDK6) encourage the Cyclin D1, D2 and D3 to phosphorylate RB1.

The growth factors and RAS, MYC encourage phosphorylation. The P15, P16 and P21 inhibit phosphorylation. P53 also plays a part by inducing the cell to produce WAF1 which triggers the P21 protein to inhibit RB1 phosphorylation.

How the RB1 Switch Works

E2F transcription factors cause proteins to be made that allow the cell to move to the next phase in the cell cycle. When RB protein is present it binds to these E2F transcription factors, stopping them from creating the proteins. When Rb protein is phosphorylated it stops Rb from binding to E2F. E2F would then be free to transcript the proteins that trigger the later phases of cell division.

The Effect of Defective RB1 genes

The cells DNA can be mutated in such a way that the RB1 protein is not created properly. Either it is built with the wrong protein sequence or else not created at all. When this happens the cell no longer waits for DNA proof reading to finish. It is as if the switch is permanently in the go position. Therefore cells can be created that have slight variations in their genes. In other words E2F doesn't bind to Rb.

What do the other genes do

P53 is a transcription factor that is stabilized somehow by the presence of DNA damage. When stable it transcripts a gene (WAF1 I think) that further transcripts the P21 protein. If there is no DNA damage then P53 is too unstable to generate the WAF1 transcription factor.

P21 is a Cyclin Kinase Inhibitor that binds to and inhibits all CDK cyclin complexes. CDKs that are inhibited are not able to bind to Rb proteins. Rb proteins therefore remain bound to E2F stopping the cell cycle from continuing.


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